Extracellular signaling molecules are typically hydrophilic and do not generally cross the hydrophobic plasma membrane of a cell by simple diffusion. Accordingly, extracellular signaling molecules are usually specifically bound by receptors that are situated on the surface of a target cell (i.e., “cell surface receptors”), and binding of a signaling molecule to a cell surface receptor modulates activity of the receptor to initiate a signal in the target cell.
Cell surface receptors play a pivotal role in almost every aspect of cell biology. Because of this role, as well as their accessibility to hydrophilic molecules, cell surface receptors have become an attractive target for drug discovery. Because peptides are relatively small, hydrophilic (making them easily formulated for administration), and can be made in large quantities either synthetically or recombinantly, peptide modulators are in particularly great demand.
Non-naturally occurring modulators of a particular cell surface receptor are typically identified from a large library of candidate agents (a library having, e.g., 106-109 different compounds). Each member of such a library is typically assayed for receptor modulatory activity, and receptor modulators are identified using the assay. Assuming the sensitivity of the assay is not limiting, the success of such screening assays primarily depends on the size of the library of candidate agents screened: the larger the library used, the more modulatory agents will be identified. Accordingly, in view of the great demand for peptide modulators of cell surface receptor activity, there is a also great demand for methods of screening large peptide libraries to identify those peptides.
However, libraries containing large numbers (e.g., 107-1012) of candidate peptides are generally prohibitively expensive to make, and, as such, are generally not available. For example, assuming that a single peptide can be synthesized in an amount suitable for assaying for the cost of $10, a library of 107 peptides would cost $100M. As such, while there is a great need for methods of identifying peptide modulators of cell surface receptor activity, this need is generally unmet because large libraries of candidate peptides are not generally available.
Accordingly, a great need still exist for methods of identifying peptide modulators of cell surface receptor activity. The invention described herein meets this need, and others.